Synthesis and regioselective ribosylation of 6,7-dichloroimidazo[4,5- b]quinolin-2-one

Article abstract of DOI:10.1021/jo982084o

The polyhalogenated benzimidazole nucleosides 2,5,6-trichloro-1-(β-D- ribofuranosyl)benzimidazole (TCRB) and the 2-bromo analogue (BDCRB) were synthesized in our laboratory and established as potent and selective antiviral agents against human cytomegalovirus (HCMV) with a novel mode of action. In an effort to study the behavior of the key substructure of these analogues in a dimensionally stretched-out manner and probe the spatial limitation of the target enzyme(s), a series of N1- and N3-ribonucleosides of imidazo[4,5-b]quinolines were designed as linear dimensional analogues. The nucleosides 6,7-dichloro-1-(β-D-ribofuranosyl)imidazo[4,5-b]quinolin-2-one and 6,7-dichloro-3-(β-D-ribofuranosyl)imidazo[4,5-b]quinolin-2-one were selected and prepared as the key intermediates in this study. During this study, a novel photoassisted annulation was developed for the synthesis of 6,7-dichloroimidazo[4,5-b]quinolin-2-one, which overcame several problems that were encountered with the literature annulation method. Regioselective ribosylations of this heterocycle were developed and gave both the N1 and the N3 isomers in high yield.

Full text of DOI:10.1021/jo982084o

J . Org. Chem. 1999, 64, 4159-4168
4159
Syn th esis a n d Regioselective Ribosyla tion of
6,7-Dich lor oim id a zo[4,5-b]qu in olin -2-on e
Zhijian Zhu,† Blaise Lippa,‡ and Leroy B. Townsend*
Department of Chemistry, College of Literature, Sciences, and Arts, and Department of Medicinal
Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109-1065
Received October 16, 1998
The polyhalogenated benzimidazole nucleosides 2,5,6-trichloro-1-(â-D-ribofuranosyl)benzimidazole
(TCRB) and the 2-bromo analogue (BDCRB) were synthesized in our laboratory and established
as potent and selective antiviral agents against human cytomegalovirus (HCMV) with a novel mode
of action. In an effort to study the behavior of the key substructure of these analogues in a
dimensionally stretched-out manner and probe the spatial limitation of the target enzyme(s), a
series of N1- and N3-ribonucleosides of imidazo[4,5-b]quinolines were designed as linear dimensional
analogues. The nucleosides 6,7-dichloro-1-(â-D-ribofuranosyl)imidazo[4,5-b]quinolin-2-one and 6,7-
dichloro-3-(â-D-ribofuranosyl)imidazo[4,5-b]quinolin-2-one were selected and prepared as the key
intermediates in this study. During this study, a novel photoassisted annulation was developed
for the synthesis of 6,7-dichloroimidazo[4,5-b]quinolin-2-one, which overcame several problems that
were encountered with the literature annulation method. Regioselective ribosylations of this
heterocycle were developed and gave both the N1 and the N3 isomers in high yield.
In tr od u ction
tion of DNA synthesis but does involve inhibition of DNA
processing.7 To further study the behavior of some key
substructures of these benzimidazole ribonucleosides in
a dimensionally stretched-out manner and probe the
spatial limitation of the binding site of the incompletely
characterized targeted enzyme(s), a series of 6,7-dichloro-
1-(â-D-ribofuranosyl)imidazo[4,5-b]quinolines (2) and 6,7-
dichloro-3-(â-D-ribofuranosyl)imidazo[4,5-b]quinolines (3),
with different substituents at the 2-positions, were
designed as dimensional analogues8 of 1 (Figure 1).
Human cytomegalovirus1 (HCMV) is a significant
pathogen for immunocomprised individuals2 such as bone
marrow3and organ transplant4 patients and individuals
with AIDS.5 Recently, a series of polyhalogenated benz-
imidazole ribonucleosides (1) were found to have potent
and selective activity against human cytomegalovirus
(HCMV).6 The lead compounds, 2,5,6-trichloro-1-(â-D-
ribofuranosyl)benzimidazole (1a) and 2-bromo-5,6-dichloro-
1-(â-D-ribofuranosyl)benzimidazole (1b), were more active
and less toxic than the clinically used agents ganciclovir
and foscarnet in cell culture studies.
A convergent approach for the generation of target
compounds would involve functional group transforma-
tions at the 2-position of certain stable nucleoside inter-
mediates, e.g., protected 6,7-dichloro-1-(â-D-ribofuranosyl)-
imidazo[4,5-b]quinolin-2-one (4) and 6,7-dichloro-3-(â-D-
ribofuranosyl)imidazo[4,5-b]quinolin-2-one (5) (Scheme
1). A facile method for the preparation of both 4 and 5
would be a regioselective ribosylation of 6,7-dichloroimi-
dazo[4,5-b]quinolin-2-one (6). Although imidazo[4,5-b]-
quinolines have been known since the 1930s, nucleosides
of imidazo[4,5-b]quinolines have not been reported in the
literature. We would now like to report9 a novel annu-
lation method for the synthesis of a derivative of imidazo-
Furthermore, both TCRB and BDCRB were found to
act by a unique mechanism that does not involve inhibi-
† Present address: Parke-Davis Pharmaceutical Research, Division
of Warner-Lambert, 2800 Plymouth Road, Ann Arbor, MI 48105.
‡ Present address: Stanford University, Department of Chemistry,
Stanford, CA 94305-5080.
(1) Alford, C. A.; Britt, W. J . Cytomegalovirus. In The Human
Herpesviruses; Roizman, B., Whitley, R. J ., Lopez, C., Eds.; Raven
Press: New York, 1993; pp 227-255.
(2) Alford, C. A.; Stagno, S.; Pass, R. F.; Britt, W. J . Congenital and
Perinatal Cytomegalovirus Infections. Rev. Infect. Dis. 1990, 12, S745-
S753.
(3) Wingard, J . R.; Piantadosi, S.; Burns, W. H.; Zahurak, M. L.;
Santos, G. W.; Saral, R. Cytomegalovirus Infections in Bone Marrow
Transplant Recipients given Intensive Cytoreductive Therapy. Rev.
Infect. Dis. 1990, 12, S793-S804.
(4) Rubin, R. H. Impact of Cytomegalovirus Infection on Organ
Transplant Recipients. Rev. Infect. Dis. 1990, 12, S754-S766.
(5) Gallant, J . E.; Moore, R. D.; Richman, D. D.; Keruly, J .; Chaisson,
R. E. et al. Incidence and Natural History of Cytomegalovirus Disease
in Patients with Advanced Human Immunodeficiency Virus Disease
Treated with Zidovudine. J . Infect. Dis. 1992, 166, 1223-1227.
(6) (a) Townsend, L. B.; Drach, J . C. and co-workers. Benzimidazole
Ribonucleosides: Design, Synthesis, Evaluation, and Mode of Action.
Presented at the Fifth Int. Conf. Antiviral Res., Vancouver, BC, 1992,
Abstracts 12, 105, 107, 108, 110. (b) Townsend, L. B.; Devivar, R. V.;
Turk, S. R.; Nassiri, M. R.; Drach, J . C. Design, Synthesis, and
Antiviral Activity of Certain 2,5,6-Trihalo-1-(â-D-ribofuranosyl)benz-
imidazoles. J . Med. Chem. 1995, 38, 4098-4105. (c) Devivar, R. V.;
Kawashima, E.; Revankar, G. R.; Breitenbach, J . M.; Freske, E. D.;
Drach, J . C.; Townsend, L. B. Benzimidazole Ribonucleosides: Design,
Synthesis, and Antiviral Evaluation of Certain 2-Alkylthio-5,6-dichloro-
1-(â-D-ribofuranosyl)benzimidazoles. J . Med. Chem. 1994, 37, 2942-
2949.
(7) (a) Underwood, M. R.; Biron, K. K.; Hemphill, M. L.; Miller, T.
J .; Stanat, S. C.; Dornsife, R. E.; Drach, J . C.; Townsend, L. B.;
Edwards, C. A.; Harvey, R. J . High Molecular Weight HCMV DNA
Does Not Properly Mature in the Presence of 2- Bromo-5,6-dichloro-
1-â-D-ribofuranosylbenzimidazole (BDCRB). Presented at the Herp-
esvirus workshop, Pittsburgh, PA, J uly 1993. (b) Underwood, M. R.;
Stanat, S. C.; Drach, J . C.; Harvey, R. J .; Biron, K. K. Presented at
the Herpesvirus workshop, Vancouver, BC, Aug 1994.
(8) Reviews on the study of dimensional probes: (a) Leonard, N. J .;
Hiremath, S. P. Dimensional Probes of Binding and Activity. Tetra-
hedron 1986, 42, 1917-1961. (b) Leonard, N. J . Dimensional Probes
of Enzyme-Coenzyme Binding Sites. Acc. Chem. Res. 1982, 15, 128-
135.
(9) Preliminary work has been published in the following com-
munications: a) Zhu, Z.; Lippa, B. S.; Townsend, L. B. A Novel Photo-
assisted Annulation Reaction for the Synthesis of 6,7-Dichloroimidazo-
[4,5-b]quinolin-2-one. Tetrahedron Lett. 1996, 37, 1937-1940. (b) Zhu,
Z.; Townsend, L. B. Regioselective Ribosylation of 6,7-Dichloroimidazo-
[4,5-b]quinolin-2-one. Tetrahedron Lett. 1996, 37, 3263-3266.
10.1021/jo982084o CCC: $18.00 © 1999 American Chemical Society
Published on Web 05/12/1999

4160 J . Org. Chem., Vol. 64, No. 11, 1999
Zhu et al.
Sch em e 1
F igu r e 1.
[4,5-b]quinolin-2-one and the subsequent study involving
regioselective ribosylation of this heterocycle.
Resu lts a n d Discu ssion
Syn th esis of th e Heter ocycle. Several methods have
been reported for the preparation of imidazo[4,5-b]-
quinolin-2-ones.10 The need for convergent and efficient
methods for the synthesis of imidazo[4,5-b]quinolin-2-
ones has become increasingly important since the dis-
covery that certain derivatives of imidazo[4,5-b]quinolin-
2-one are potent inhibitors of blood platelet low cAMP
phosphodiesterase and induced aggregation and exhibit
antithrombotic activity in animal models.10c Except for
one example,10b approaches for the synthesis of this
parent structure have all involved a closure of the central
ring as the final synthetic transformation either from
5-[(2-nitrophenyl)methyl]-2,4-imidazolidinediones10c,d or
from 5-[(2-nitrophenyl)methylene]-2,4-imidazolidinedi-
ones10a,d (9). In an improved method recently reported by
Meanwell and co-workers,10c,d a Horner-Wadsworth-
Emmons type of olefin-forming reaction was used as the
key step in the preparation of imidazo[4,5-b]quinolin-2-
ones (10) (Scheme 2). By this method, 10 can be gener-
ated rapidly and reliably in excellent yields under mild
conditions.
Sch em e 2a
a
Key: (1) base; (2) (a) Pd/C, H2, (b) TsOH, MeOH, (c) I2, MeOH,
reflux.
Sch em e 3a
To use the approach reported by Meanwell and co-
workers,10d 4,5-dichloro-2-nitrobenzaldehyde11 (14) was
prepared from 4,5-dichloro-2-nitroaniline (11) through
4,5-dichloro-2-nitrobenzonitrile (12) in an overall 50%
yield (Scheme 3). The preparation of 12 from 11 was
improved from the reported12 20% yield to 94% yield
through the corresponding diazonium tetrafluoroborate
salt by a nonaqueous diazotization.13 The condensation
between 4,5-dichloro-2-nitrobenzaldehyde (14) and di-
(10) (a) Reid, W.; Grabosch, J . J . Note on N-substituted 2,3-
diaminopyridines. Chem. Ber. 1956, 89, 2684-2687. (b) Connors, T.
A.; Ross, W. C. J .; Wilson, J . G. Aryl-2-halogenoalkylamines. Part XIX.
Some N,N-di-2-chloroethylaminophenyl- and Phenylalkyl Hydantions
and Related Amino Acids. J . Chem. Soc. 1960, 2994-3007. (c)
Meanwell, N. A.; Roth, H. R.; Smith, E. C. R.; Wedding, D. L.; Wright,
J . J . K.; Fleming, J . S.; Gillespie, E. 1,3-Dihydro-2H-imidazo[4,5-b]-
quinolin-2-ones, Inhibitors of Blood Platelet cAMP phosphodiesterase
and Induce Aggregation. J . Med. Chem. 1991, 34, 2906-2916. (d)
Meanwell, N. A.; Roth, H. R.; Smith, E. C. R.; Wedding, D. L.; Wright,
J . J . K. Diethyl 2,4-Dioxoimidazolidine-5-phosphonates: Horner-
Wadsworth-Emmons Reagents for the Mild and Efficient Preparation
of C-5 Unsaturated Hydantion Derivatives. J . Org. Chem. 1991, 56,
6897-6904.
a
Key: (1) (a) t-BuONO, BF3‚OEt2, (b) NaCN, CuCN, 94%
overall; (2) (a) BH3‚THF, (b) NaNO2, AcOH, H2O, (c) NaOH, H2O,
66%; (3) PCC, CH2Cl2, 80%; (4) diethyl 2,4-dioxoimidazolidine-5-
phosphonate, Et3N, CH3CN, quantitative; (5) (a) Pd/C, H2, (b)
TsOH, MeOH, (c) I2, MeOH, reflux.
ethyl 2,4-dioxoimidazolidine-5-phosphonate,10d in the
presence of triethylamine in acetonitrile, gave 5-[(4,5-
dichloro-2-nitrophenyl)methylene]imidazolidine-2,4-di-
one (15) as a mixture of Z/E isomers (3/1) in a quantita-
tive yield. The pure Z isomer ((Z)-15) was isolated by a
collection of the precipitate directly from the reaction
mixture in a 63% yield. The pure E isomer ((E)-15) was
obtained in 14% yield by a recrystallization of the
remaining Z/E mixture from 1,4-dioxane. The regio-
(11) Horner, J . K.; Henry, D. W. Analogues of 3-Amino-7-chloro-
1,2,4-benzotriazin-1-oxide as Antimalarial Agents. J . Med. Chem. 1968,
11, 946-949.
(12) Rosowsky, A.; Marini, J . L.; Nadel, M. E.; Modest, E. J .
Quinazolines. VI. Synthesis of 2,4-Diaminoquinazolines from Anthra-
nilonitriles. J . Med. Chem. 1970, 13, 882-886.
(13) Doyle, M. P.; Bryker, W. J . Alkyl Nitrite-Metal Halide Deami-
nation Reactions 6. Direct Synthesis of Arenediazonium Tetrafluoro-
borate Salts from Aromatic Amines, tert-butylnitrite, and Boron
Trifluoride Etherate in Anhydrous Media. J . Org. Chem. 1979, 44,
1572-1574.

Ribosylation of 6,7-Dichloroimidazo[4,5-b]quinolin-2-one
J . Org. Chem., Vol. 64, No. 11, 1999 4161
Sch em e 4a
close to give 6 during the double-bond photoisomeriza-
tion, it would provide an additional driving force to push
the photoequilibrium in the direction of the E isomer.
Indeed, when 16, in acetic acid, was irradiated by a
medium-pressure mercury lamp at room temperature, a
40% yield of 6 was isolated. It was assumed that the short
wavelength portion of the medium-pressure mercury
lamp could be implicated in the low yield and the side
products. A UV spectrum of 16 revealed peaks at 230,
315, and 374 nm. The UV peak centered at 374 nm slopes
down to 440 nm. We decided to monitor the peak at 374
nm for our study on the double-bond isomerization. When
a cupric sulfate/ammonium hydroxide solution was se-
lected as the filter solution,16b to filter off light with
wavelengths shorter than 405 nm, 6 was obtained in a
90% yield after 60 h irradiation in acetic acid at 25 °C.
The assumption that the peak at 374 nm could be
attributed to the double bond isomerization was also
confirmed by using potassium chromate/ammonium hy-
droxide solution16b as the UV light filter solution. This
solution can filter off light with wavelengths shorter than
450 nm, and under this condition no product was formed.
Thus, a novel photoassisted annulation reaction was
developed for the synthesis of imidazo[4,5-b]quinolin-2-
ones that avoids a reduction of the double bond by
stringent hydrogenation conditions and should tolerate
a variety of functional groups. By this method, 6,7-
dichloroimidazo[4,5-b]quinolin-2-one (6) was synthesized
from 15 in an overall 89% yield.
Selective Ribosyla tion . Although glycosylation of
imidazo[4,5-b]quinolin-2-ones or the imidazo[4,5-b]quino-
lines, per se, was unknown, the ribosylation of a struc-
turally related ring system, imidazo[4,5-b]pyridine, was
well documented.17 The glycosylation of imidazo[4,5-b]-
pyridine and its derivatives has been studied by using
different methods, including the mercury salt method,
the acid-catalyzed fusion method, the direct condensation
method, and the silyl-Hilbert-J ohnson method. In most
of these studies, the N-3 isomers were found to be the
major product. In a study on the ribosylation of imidazo-
[4,5-b]pyridine by Itoh and co-workers,18 the N-4 ribo-
nucleoside could also be obtained as the major product
under the kinetic conditions dictated by the silyl-
Hilbert-J ohnson method.
a
Key: (1) (a) NaOH, MeOH, (b) 10% HCl, quantitative; (2) Fe,
FeSO4, MeOH, H2O, reflux, 99%; (3) hν, AcOH, rt, 90%.
chemical assignment was based on a previous study14
that demonstrated that, in general, in the NMR spec-
1
trum, the olefinic proton of the Z isomer is downfield from
the olefinic proton of the E isomer.
When 15 (mixture of E and Z) was subjected to the
literature annulation method involving hydrogenation
catalyzed by 10% Pd/C in DMF followed by an acid-
catalyzed ring closure and an oxidative aromatization, 6
was obtained in very low yield. A H NMR spectrum of
the crude products revealed that severe dechlorination
had occurred.
1
We then decided to proceed with the reduction of the
nitro group and the double bond in two separate steps.
The nitro group of (Z)-15 was selectively reduced by an
iron reduction to give (Z)-5-[(2-amino-4,5-dichlorophenyl)-
methylene]imidazolidine-2,4-dione (16) in 99% yield. On
the other hand, when E-15 was subjected to the same
iron reduction conditions, compound 6 was obtained
instead of the reduced form of E-15. However, this rather
insoluble solid (6) was very difficult to separate from the
solid mixture of Fe and FeOn. This makes a direct
reduction of the nitro group of the Z/E mixture of 15 less
productive due to the loss of 6 during the workup. Other
methods for a selective reduction of the nitro group of
the Z/E mixture of 15 were studied, including hydrogena-
tion catalyzed by palladium on carbon or Raney nickel,
reduction by stannous chloride, etc. However, none of
these reduction conditions gave a clean reaction. It was
reported by Meanwell and co-workers that a Z/E mixture
of (Z)-15 and (E)-15 could be isomerized completely to
the Z isomer under alkaline conditions.10d
A selective iron reduction of the nitro group then gave
16 in 99% yield for the two steps (Scheme 4). Reduction
of the double bond of 16 was then attempted using
various hydrogenation conditions. It was found that
palladium on carbon or Raney nickel would not reduce
the double bond without effecting a dehalogenation, and
no apparent reaction was observed when chlorotris-
(triphenylphosphine)rhodium(I)15 was used as the cata-
lyst under normal hydrogenation conditions.
The ribosylation of 6,7-dichloroimidazo[4,5-b]quinolin-
2-one (6) was first studied by a direct acid-catalyzed
condensation. When 6 was treated with 2,3,5-tri-O-
benzoyl-1-O-acetyl-â-D-ribofuranose (TBAR), catalyzed by
stannic chloride in acetonitrile at 50 °C for 4 h, 6,7-
dichloro-3-(2,3,5-tri-O-benzoyl-â-D-ribofuranosyl)imidazo-
[4,5-b]quinolin-2-one (5a ) was obtained in a 89% yield
(Scheme 5). This regioselectivity is in agreement with
that reported17,18 for imidazo[4,5-b]pyridine.
The ribosylation of 6 was then studied by using the
silyl-Hilbert-J ohnson method.19 Silylation of the het-
To rotate the 2,4-dioxoimidazolidine moeity of (Z)-15
to the appropriate juxtaposition for ring closure without
reducing the double bond, double-bond photoisomeriza-
tion16 was considered. We surmised that if 16 could ring
(16) (a) Ninomiya, I.; Naito, T. Photochemical Synthesis; Academic
Press: London, New York, 1989; Chapter 4. (b) Hammond, G. S.;
Saltiel, J .; Lamola, A. A.; Turro, N. J .; Bradshaw, J . S.; Cowan, D. O.;
Counsell, R. C.; Vogt, V.; Dalton, C. Mechanisms of Photochemical
Reactions in Solution. XXII. Photochemical Cis-trans Isomerization.
J . Am. Chem. Soc. 1964, 86, 3197-3217.
(17) For a general review on the glycosylation of imidazo[4,5-b]-
pyridine derivatives: Revankar, G. R.; Robins, R. K. In The Chemistry
of Nucleosides and Nucleotides; Townsend, L. B., Ed.; Plenum Press:
New York and London, 1991; Vol. 2, pp 168-180.
(18) Itoh, T.; Mizumo, Y. Product Distribution in the Ribosylation
Reactions of Adenine and 1-Deazapurine in the Presence of Stannic
Chloride. Heterocycles 1976, 5, 285-292.
(14) Tan, S. F.; Ang, K.; Fang, Y. F. (Z)- and (E)-5-arylmethylene-
hydantoins: Spectroscopic Properties and Configuration Assignment.
J . Chem. Soc., Perkin Trans. 2 1986, 1941-1944.
(15) Takata, H.; Noyori, R. Homogeneous catalytic hydrogenation
of CdC and C≡C. in Comprehensive Organic Synthesis; Trost, B.,
Fleming, I., Eds; Pergamon Press: New York, 1991; Vol. 8, pp 443-
469.

4162 J . Org. Chem., Vol. 64, No. 11, 1999
Zhu et al.
Sch em e 5a
Sch em e 7a
a
Key: (1) (a) BSA, CH3CN, rt, (b) TBAR, TMSOTf, 50 °C, 29%;
(2) NaOMe, MeOH, 48%.
a
Key: (1) TBAR, SnCl4, CH3CN, 50 °C, 89%; (2) NH3, MeOH,
A systematic study was then initiated to study the effect
of temperature, solvent system, and Lewis acid on the
distribution of the sites of ribosylation (Scheme 6, Table
1).
94%.
Sch em e 6a
In general, when the ribosylations were conducted
under Vorbruggen conditions21 using trimethylsilyl tri-
fluoromethanesulfonate (TMSOTf) as the Lewis acid
instead of stannic chloride, a dramatic increase in the
formation of 4a was observed. A highly regioselective
ribosylation was achieved to give a 20/1 ratio of 4a /5a in
a combined 85% yield (Table 1, entry 5) when the reaction
was catalyzed by TMSOTf in ClCH2CH2Cl/CH3CN (3/4)
at 70 °C for 1 h. When the polarity of the solvent system
was decreased (ClCH2CH2Cl/CH3CN, 3/1), a decrease of
regioselectivity was observed (Table 1, entry 6). However,
when acetonitrile was used as the only solvent, a mixture
of 4a and 5a in a ratio of 4.2/1 was obtained in a
combined 76% yield (Table 1, entry 8). This low regiose-
lectivity is presumably due to the incomplete silylation
in acetonitrile. It was found that a high temperature was
also required for the ribosylation when TMSOTf was used
as the Lewis acid. It is apparent that the type of Lewis
acid, solvent, and temperature are all important for the
regioselective formation of the N1-riboside 4a .
Mech a n ism for th e Regioselective F or m a tion of
4a . When the silyl-Hilbert-J ohnson ribosylation was
conducted at low temperature (Table 1, entries 3, 4, and
7), the ribosylation proceeded at a lower rate and the
generation of N4-riboside (17a ) was observed first, very
shortly after the addition of the Lewis acids. However,
both 4a and 5a began to appear shortly after the
formation of 17a . With a continuation of the reactions,
the amount of 4a and 5a continued to increase while the
amount of 17a was maintained at a relatively constant
level until gradually disappearing toward the end of the
reactions. By quenching the ribosylations a short time
after the addition of the Lewis acids, a small amount of
17a was isolated (Scheme 7). When treated with BSA and
TMSOTf at 70 °C in ClCH2CH2Cl/CH3CN (3/4), 17a was
converted to 4a and 5a in a ratio of 15/1 in a combined
83% yield. And when 17a was treated with BSA and
stannic chloride under the same conditions, 4a and 5a
were obtained in a ratio of 4.7/1 in a combined 86% yield
(Scheme 8). This would suggest that 17a is a kinetic
product under the silyl-Hilbert-J ohnson conditions.
Furthermore, the high regioselective transformation of
17a to 4a in the presence of TMSOTf and the observed
initial formation of 17a during the ribosylation implied
the possible key role of 17a in the regioselective genera-
tion of 4a .
a
Key: (1) see Table 1; (2) NH3, MeOH, 97%.
Ta ble 1. Ribosyla tion of Silyla ted 6 w ith TBAR
Lewis
acida
ClCH2CH2Cl/
CH3CN
T
(°C)
time
(h)
yieldc
(%)
entry
4a /5a b
1
2
3
4
5
6
7
8
SnCl4
SnCl4
SnCl4
SnCl4
TMSOTf
TMSOTf
TMSOTf
TMSOTf
3/4
3/1
3/1
0/1
3/4
3/1
3/4
0/1
70
70
rt
1
1
6
6
1
1
5
1
2.1/1
1.8/1
1.5/1
2.0/1
20/1d
5.2/1
17/1
65
75
61
60
85
86
68
76
rt
70
70
50
70
4.2/1
a
Two equivalents of a Lewis acid were used in all cases. b Ratios
determined from HPLC analysis. c Combined yield of 4a and 5a
isolated from flash chromatography. Ratio from isolated prod-
ucts.
d
erocycle was conducted by using N,O-bis(trimethylsilyl)-
acetamide (BSA).20 It was found that silylated 6 was
insoluble in acetonitrile but soluble in 1,2-dichloroethane.
However, in 1,2-dichloroethane hardly any ribosylation
was detected when silylated 6 was treated with TBAR
in the presence of a Lewis acid. Thus, the ribosylation
reaction was carried out by first silylating 6 in 1,2-
dichloroethane followed by diluting the reaction with a
certain amount of acetonitrile before the addition of
TBAR and a Lewis acid. In this way, a homogeneous
solution was maintained throughout the reaction and
produced a smooth ribosylation. When silylated 6 was
condensed with TBAR in the presence of stannic chloride
in 1,2-dichloroethane/acetonitrile (3/4) at 70 °C, a mixture
of the N3- and N1-ribonucleoside was obtained (Scheme
6, Table 1, entry 1). Surprisingly, the N1 isomer, 6,7-
dichloro-1-(2,3,5-tri-O-benzoyl-â-D-ribofuranosyl)imidazo-
[4,5-b]quinolin-2-one (4a ), was found to be the major
product. This is different from the ribosylation of imidazo-
[4,5-b]pyridine18 using the silyl-Hilbert-Johnson method.
(19) For a general review on the Hilbert-J ohnson glycosylations:
Pliml, J .; Prystas, M. The Hilbert-J ohnson Reaction of 2,4-Dialkoxy-
pyrimidines with Halogenoses. Adv. Heterocycl. Chem. 1967, 8, 115-
142.
(20) Dudycz, L.; Wright, G. E. A Simple One-pot Method for
6-Oxopurine Ribonucleoside Synthesis: Control and Mechanism of
Isomer Distribution. Nucleosides Nucleotides 1984, 3, 33-44.
(21) (a) Vorbruggen, H.; Krolikiewicz, K.; Bennua, B. Nucleoside
Synthesis XII. Nucleoside Synthesis with Trimethylsilyl Triflate and
Perchlorate as Catalysts. Chem. Ber. 1981 114, 1234-1255. (b)
Vorbruggen, H.; Bennua, B. Nucleoside Synthesis XXV. A New
Simplified Nucleoside Synthesis. Chem. Ber. 1981, 114, 1279-1286.

Ribosylation of 6,7-Dichloroimidazo[4,5-b]quinolin-2-one
J . Org. Chem., Vol. 64, No. 11, 1999 4163
Sch em e 8
Sch em e 9
Transglycosylation among regioisomers of nucleosides
and the reversibility of glycosylation have been reported
in many systems.22 The overall yield of a particular
isomer under thermodynamic conditions is believed to
depend on the relative stability of the isomer. Among the
regioisomers of imidazo[4,5-b]pyridine ribonucleoside, the
N3 isomer was considered17,18 as the most stable isomer
since it was found to be the major product both under
the thermodynamic ribosylation conditions and through
the transglycosylation of the corresponding N4-isomer.
By analogy, compound 5a (N3-isomer) would be more
stable than 4a (N1-isomer). However, no reaction was
observed when either 4a or 5a was treated with BSA (2
equiv) and TMSOTf (2 equiv) in acetonitrile/1,2-dichlo-
roethane (1/1) at 75 °C for 12 h. Also, no reaction was
observed when 4a was treated with stannic chloride in
acetonitrile at 50 °C for 24 h. This suggested that both
4a and 5a are stable products under the applied ribosyl-
ation conditions and stability is, most likely, not the
determining factor in the regioselective formation of 4a .
On the basis of the implicit role of 17a in the formation
of 4a , we proposed that this unexpected high regioselec-
tive formation of 4a could undergo the following mech-
anism (Scheme 9). First, ribosylation of silylated 6
occurred at the N4 position (to give 18), and this was
followed by a second ribosylation. The second ribosylation
preferably took place at the N1 position due to the block
of the N3 position by the first ribosyl moiety and gave
the corresponding 1,4-diribosylated nucleoside (19a ). The
rather labile ribosyl moiety at the N4 position of 19a was
then removed in the presence of the Lewis acid to give
the N1 ribonucleoside 4a .
Sch em e 10a
After a reexamination of this ribosylation, we indeed
isolated a small quantity of 1,4-diribosylated nucleoside
19a (details of the structure assignment is discussed in
the next section). When 19a was treated with TMSOTf
at room temperature, it was completely converted to 4a
in less than 5 min. To further prove the mechanism, 17a
was silylated by BSA followed by the addition of TBAR
and TMSOTf at room temperature (Scheme 10). Monitor-
ing the reaction by TLC indicated that 19a was formed
first, before the generation of 4a . After 3 h at room
temperature, 19a (27%) was obtained with 4a (5%) and
a recovery of 17a (50%). When the reaction time was
extended to 3.5 h, 19a and 4a were obtained in a 42%
and 26% yield, respectively, with the recovery of 17a
(18%). This clearly indicated that the selective formation
of 4a from 17a was achieved through the generation of
the diribonucleoside 19a .
a
Key: (1) (a) BSA, CH3CN, rt, (b) TBAR, TMSOTf; (2) NaOMe,
MeOH, 66%; (3) TMSOTf, CH3CN, rt, 90%.
Regioch em ica l Assign m en t. To make the regio-
chemical assignment of compounds 4a , 5a , and 17a , they
were first deprotected by using either methanolic am-
monia or sodium methoxide in methanol to give the
corresponding ribonucleosides 6,7-dichloro-1-(â-D-ribo-
furanosyl)imidazo[4,5-b]quinolin-2-one (4b), 6,7-dichloro-
3-(â-D-ribofuranosyl)imidazo[4,5-b]quinolin-2-one (5b), and
6,7-dichloro-4-(â-D-ribofuranosyl)imidazo[4,5-b]quinolin-
2-one (17b), respectively. The UV spectra of compounds
4b, 5b, 17b, and 6,7-dichloroimidazo[4,5-b]quinolin-2-one
(6) were obtained in methanol, pH 11 buffer, and pH 1
buffer. The UV spectra of compound 4b and 5b were
found to be quite similar to that of 6. However, the UV
spectrum of 17b was significantly different from that of
6. This indicated that compound 17b was the N4-
ribosylated nucleoside since substitution on N4 would
significantly alter the aromaticity of the ring. However,
no distinguishible difference was observed between com-
(22) (a) See refs 18, 20, and 21b. (b) Garner, P.; Ramakanth, S. A.
Regiocontrolled Synthesis of N7- and N9-Guanine Nucleoside. J . Org.
Chem. 1988, 53, 1294-1298. (c) Wood, S. G.; Dalley, N. K.; George, R.
D.; Robins, R. K.; Revankar, G. R. Synthesis and Structural Studies
of Certain Novel Imidazo[1,2-b]pyrazole Nucleosides. J . Org. Chem.
1984, 49, 3534-3540.

4164 J . Org. Chem., Vol. 64, No. 11, 1999
Zhu et al.
F igu r e 2. NOE difference experiments. *In DMSO-d6 at room
temperature. **In CD3OD, at room temperature.
pound 4b and 5b in acidic, basic, and neutral media. This
excluded the possibility of using UV for the regiochemical
assignment of compound 4b and 5b. The carbon-13
spectra showed the same trend as the UV spectra. The
13C spectra of 4b and 5b showed similar patterns and
were quite different from that of 17b in the aromatic
region.
Besides support from the UV spectrum, further proof
of the regiochemistry of 17b came from the NOE differ-
ence experiments (Figure 2). First, for the three aromatic
protons of 17b, the peak at 8.63 ppm does not have any
NOE with the other two aromatic protons, while the peak
at 8.22 ppm showed NOE enhancements with a peak at
7.40 ppm. This indicated that the peak at 8.63 ppm is
H5 and the peaks at 8.22 and 7.40 ppm are either H8 or
H9. When H5 was irradiated, a 6.1% enhancement of H2′
and a 9.9% enhancement of H1′ were observed while
irradiation of H1′ gave a 7.5% enhancement of H5. This
provided further proof that the ribosyl moiety of 17b was
residing at N4. For compound 5b, no NOE enhancement
was observed between any aromatic protons and any
protons on the ribosyl moiety. For compound 4b, when
the aromatic proton at 8.21 ppm was irradiated, a 3.6%
enhancement of H2′ and a 1.4% enhancement of H1′ were
observed while irradiation of H1′ gave a 1.2% enhance-
ment of the peak at 8.21 ppm. NOE enhancement was
also observed between aromatic protons at 8.21 and 8.15
ppm while no NOE enhancement was observed for the
aromatic proton at 8.06 ppm with the other aromatic
protons. This indicated that the proton at 8.06 ppm is
H5 and the protons at 8.21 and 8.15 ppm are either H8
or H9. This provides evidence that the site of ribosylation
of 4b could be at N1.
To unequivocally determine the position of ribosylation
for compound 4b and 5b, a study of three-bond 13C-1H
spin-spin long-range coupling between the proton at the
anomeric position of the nucleoside and the R carbons of
the heterocycle next to the glycosylation site23 was
conducted. To make this determination, the entire aro-
(23) Cline, B.; Fagerness, P. E.; Panzica, R. P.; Townsend, L. B. The
use of Carbon-13 Magnetic Resonance Chemical Shifts and Long-range
13C-1H Constants for Assigning the Site of Glycosylation of Nitrogen
Heterocycles. J . Chem. Soc., Perkin Trans. 2 1980, 1586-1591.

Ribosylation of 6,7-Dichloroimidazo[4,5-b]quinolin-2-one
J . Org. Chem., Vol. 64, No. 11, 1999 4165
matic region of the 13C NMR spectra of both 4b and 5b
were first unequivocally assigned by using the long-range
1H-13C selective decoupling method.24 The carbon-13
assignments25 and the 13C-1H coupling constants for the
aromatic carbons of 4b and 5b are listed in Table 2.
When the anomeric proton of 4b was irradiated,
carbons C2 and C9a were decoupled, which confirmed
that the ribosyl moiety of 4b was attached to the N1
position. On the other hand, when the anomeric proton
of 5b was irradiated, carbon C2 and C3a were decoupled,
which indicated that the ribosyl moiety of 5b was
attached at the N3 position.
The protected diribosylated nucleoside 19a was depro-
tected by the use of sodium methoxide in methanol to
give 6,7-dichloro-1-(â-D-ribofuranosyl)-4-(â-D-ribofurano-
syl)imidazo[4,5-b]quinolin-2-one (19b). The NOE en-
hancements between H9 and H1′ together with the NOE
enhancements between H5 and H1′′ or H2′′ indicated that
the two ribosyl moieties are located at the N1 and N4
positions (Figure 2). The NOE enhancements between
H1′ and H4′, and H1′′ and H4′′ confirmed that both
anomeric bonds of the two ribosyl moieties have the
â-configuration.
carried out in a 1000 mL photochemical reaction assembly with
450 W medium-pressure mercury lamp (cat. no. 7825-34).
4,5-Dich lor o-2-n itr oben zon itr ile (12). Boron trifluoride
etherate (9.2 mL, 75 mmol) was placed into a 1000 mL three-
neck flask equipped with a thermometer and two dropping
funnels under an argon atmosphere. The solution was cooled
to -10 °C by a dry ice-acetone bath. A solution of 4,5-dichloro-
2-nitroaniline (11, 10.35 g, 50 mmol, Aldrich) in a mixture of
dry THF (80 mL) and dry dichloromethane (160 mL) was
added dropwise to the reaction solution at a rate that the
temperature was maintained below -5 °C to give a yellow
suspension. After the temperature was returned to -10 °C,
tert-butyl nitrite (8 mL, 60 mmol) in dry dichloromethane (60
mL) was added at a rate sufficient to maintain the temperature
around -10 °C. After the addition, the solution became clear
and remained clear for about 5 min before a large amount of
a yellow precipitate appeared. The suspension was stirred
under -10 °C for an additional 20 min and then in an ice bath
for 40 min followed by the addition of hexane (200 mL). The
solid was collected by filtration, washed with ether, and dried
under vacuum at room temperature to give (4,5-dichloro-2-
nitrophenyl)diazonium tetrafluoroborate (13.8 g, 90 %) as a
slightly yellow solid. Without further purification, the salt was
used for the following reaction.
The diazonium tetrafluoroborate salt (25.5 g, 83.3 mmol)
was added in portions over a period of 15 min to a solution of
cuprous cyanide (20 g, 222 mmol) and sodium cyanide (28 g,
570 mmol) in water (200 mL) in a 500 mL three-neck flask
equipped with a mechanical stirrer in an ice bath. During the
addition, a small amount of ice was added frequently for
efficient cooling. The suspension was stirred continuously in
an ice bath for an additional 2 h and then at room temperature
overnight. The brown suspension was extracted with ether
(1000 mL), and the ether solution was washed with a saturated
sodium chloride solution and dried over anhydrous sodium
sulfate. The ether solution was concentrated to about 60 mL
and then allowed to stand in a refrigerator (5 °C) for 1 h. The
solid was collected by filtration and dried under vacuum at
room temperature to give 4,5-dichloro-2-nitrobenzonitrile (12,
15.14 g, 84%) as a brown solid. The filtrate was further purified
by silica gel flash chromatography (2 × 6 cm) with elution by
5% ethyl acetate in hexane. The appropriate fractions, as
identified by TLC, were collected, the solvent was evaporated,
and the solid was dried under vacuum at room temperature
to give an additional 1.7 g of 12 (10%) as a yellow solid. The
total yield was 94%: mp 125-127 °C (lit.12 mp 129-130 °C);
1H NMR (CDCl3) δ 8.46 (s, 1H), 8.02 (s, 1H); 13C NMR (CDCl3)
δ 146.6, 140.0, 139.0, 136.3, 127.5, 113.1, 107.2.
4,5-Dich lor o-2-n itr oben zen em eth a n ol (13). Borane‚THF
complex in THF (1 M, 137 mL, 137 mmol) was added dropwise
through a dropping funnel to a solution of 4,5-dichloro-2-
nitrobenzonitrile (12, 14.9 g, 68.5 mmol) in dry THF (90 mL)
in a 1000 mL three-neck flask under an argon atmosphere.
The solution was stirred at room temperature overnight to give
a clear dark solution. Hydrogen chloride (10 %, 171 mL) was
added cautiously to the reaction solution. After the addition,
the solution was heated at reflux for 30 min to afford a clear
orange solution. The THF was removed under reduced pres-
sure to give a yellow suspension. The suspension was extracted
by diethyl ether (2 × 200 mL), and the ether layer, containing
byproducts (TLC, Rf ) 0.7-0.8, 40% AcOEt in hexane), was
discarded. The aqueous suspension was neutralized by the
addition of concentrated ammonium hydroxide and then
extracted with ether (2 × 200 mL). The ether layer was washed
with saturated sodium chloride and dried over anhydrous
sodium sulfate. The ether was evaporated, and the solid was
dried under vacuum at room temperature overnight to give
4,5-dichloro-2-nitrobenzylamine (12.6 g, 83.6 %) as a yellow
solid that was immediately used for the next step since
exposure to air for a period of time will produce side prod-
ucts.: 1H NMR (CDCl3) δ 8.14 (s, 1H), 7.65 (s, 1H), 4.14 (s,
2H), 1.66 (bs, 2H).
Con clu sion s
A novel photoassisted annulation method was devel-
oped for the preparation of 6,7-dichloroimidazo[4,5-b]-
quinolin-2-one (6), which is expected to accommodate a
variety of functional groups. Regioselective ribosylation
methods were developed to give both the N1 and the N3
ribonucleosides of 6,7-dichloroimidazo[4,5-b]quinolin-2-
one in high yield. This represented the first synthesis of
a ribonucleoside of imidazo[4,5-b]quinolines. A study of
the mechanism for the regioselective formation of 4a
under Vorbruggen conditions revealed, for the first time,
that steric requirements of a sequential ribosylation,
instead of relative stability, determine the site of final
ribosylation. The possible application of this ribosylation
mechanism to other heterocyclic ring systems is now
under investigation. The synthesis of the target dimen-
sional analogues (2 and 3) from 4a and 5a together with
an evaluation of their biological activities will be reported
in a separate paper.
Exp er im en ta l Section
Gen er a l P r oced u r es. Melting points were taken on a
melting point apparatus and are uncorrected. The silica gel
used for chromatography was silica gel 60 230-400 mesh. Thin
layer chromatography (TLC) was performed on prescored
SilicAR 7GF plates. Compounds were visualized by illumina-
tion under UV light (254 nm). Evaporations were carried out
under reduced pressure (water aspirator) with the bath
temperature below 40 °C, unless specified otherwise. UV
spectra were performed on a UV/vis spectrophotometer. Nuclear
magnetic resonance (NMR) spectra were determined at 360
MHz. The chemical shift values are expressed in δ values
(parts per million) relative to the standard chemical shift of
TMS or the solvent used. Elemental analyses were performed
by a commercial laboratory. Photoreaction experiments were
(24) (a) Kalinowski, H.-O.; Gerger, S.; Braun, S. Carbon-13 Spec-
troscopy; J ohn Wiley & Sons Inc.: New York, 1986; pp 57-59. (b) Bock,
K.; Pederson, C. Assignment of Long-range Carbon-proton Couplings
Through Selective Proton Decoupling. J . Magn. Reson. 1977, 5, 227-
230.
Sodium nitrite (5.93 g, 86.0 mmol) in water (22.5 mL) was
added dropwise into the solution of 4,5-dichloro-2-nitrobenzyl-
amine (12.6 g, 57.3 mmol) in acetic acid (43 mL) and water
(25) See the Supporting Information for details.

4166 J . Org. Chem., Vol. 64, No. 11, 1999
Zhu et al.
(28.8 mL) in an ice bath with vigorous stirring. After the
complete addition, the suspension was continuously stirred in
an ice bath for 10 min and then at room temperature for 15
min. The suspension was extracted with dichloromethane (3
× 100 mL). The combined dichloromethane extracts were dried
over anhydrous sodium sulfate and evaporated to dryness (first
by an aspirator and then by an oil pump) at room temperature.
The solid was redissolved in methanol (64 mL), and 1 N sodium
hydroxide (64 mL) was added over a period of 20 min with
vigorous stirring. After the addition, the solution was continu-
ously stirred for an additional 10 min at room temperature
and then extracted with dichloromethane (3 × 100 mL). The
Con ver sion of a m ixtu r e of (Z)-/(E)-5-[(4,5-d ich lor o-2-
n itr op h en yl)m eth ylen e]im id a zolid in e-2,4-d ion e ((Z)-/(E)-
15) to (Z)-15. A sodium hydroxide solution (50%) was added
dropwise to a yellow suspension of (Z)- and (E)-5-[(4,5-dichloro-
2-nitrophenyl)methylene]imidazolidine-2,4-dione ((Z)-/(E)-15,
3/1, 5.54 g) in methanol (280 mL) at room temperature until
a clear red solution was generated. The solution was stirred
at room temperature for an additional 10 min. The reaction
solution was then neutralized by the dropwise addition of
hydrochloric acid (6 N) to give a yellow suspension. The
methanol was removed under reduced pressure, and water
(500 mL) was added to the residue. The suspension was stirred
at room temperature for 3 h and allowed to stand at 5 °C for
2 h. The solid was collected by filtration and dried under
vacuum to give (Z)-5-[(4,5-dichloro-2-nitrophenyl)methylene]-
imidazolidine-2,4-dione ((Z)-15, 5.5 g, quantitative) as a yellow
combined dichloromethane extracts were washed with
a
saturated sodium chloride solution, dried over anhydrous
sodium sulfate, and evaporated to dryness. The solid was
subjected to silica gel flash chromatography (5 × 15 cm) with
elution by 5% ethyl acetate in hexane and then 20% AcOEt in
hexane to give 4,5-dichloro-2-nitrobenzenemethanol (13, 9.9
g, 79%) as a yellow solid. A small amount of the sample was
recrystallized from ethyl acetate and hexane for analysis: 1H
NMR (CDCl3) δ 8.25 (s, 1H), 7.95 (s, 1H), 5.02 (s, 2H), 2.39
(bs, 1H). Anal. Calcd for C7H5Cl2NO3: C, 37.84; H, 2.25; N,
6.31. Found: C, 38.02; H, 2.22; N, 6.17.
1
solid. The purity of (Z)-15 was verified by H NMR.
(Z)-5-[(2-Am in o-4,5-d ich lor op h en yl)m eth ylen e]im id a -
zolid in e-2,4-d ion e (16). (Z)-5-[(4,5-Dichloro-2-nitrophenyl)-
methylene]imidazolidine-2,4-dione ((Z)-15, 4.07 g), iron powder
(12 g), and ferric sulfate (1.2 g) were heated in a mixture of
water (200 mL) and methanol (100 mL) at reflux temperature
for 2 h with mechanical stirring. The methanol was removed
under reduced pressure, and water (200 mL) was added. The
suspension was extracted with ethyl acetate (3 × 500 mL).
The combined ethyl acetate extracts were washed with a
saturated sodium chloride solution and then dried over
anhydrous sodium sulfate. The solvent was evaporated to give
(Z)-5-[(2-amino-4,5-dichlorophenyl)methylene]imidazolidine-
2,4-dione (16, 3.63 g, 99%) as a yellow solid. A small amount
of sample was recrystallized from ethanol for analysis: mp
dec above 250 °C; 1H NMR (DMSO-d6) δ 11.20 (s, 1 H), 10.60
(s, 1 H), 7.37 (s, 1 H), 6.88 (s, 1 H), 6.30 (s, 1H), 5.81 (bs, 2 H);
13C NMR (DMSO-d6) δ 165.1, 155.5, 147.5, 131.0, 130.0, 128.9,
117.5, 117.0, 115.7, 102.7; UV [λmax, nm (ꢀ)] (MeOH) 374.0
(2040), 342.4 (610), 306.4 (5450), 217.0, (16400). Anal. Calcd
4,5-Dich lor o-2-n itr oben za ld eh yd e (14). A solution of 4,5-
dichloro-2-nitrobenzenemethanol (13, 11.41 g, 51.6 mmol) in
HPLC-grade dichloromethane (260 mL) was added, with
stirring, to a mixture of pyridinium chlorochromate (22.7 g,
105.3 mmol) in HPLC-grade dichloromethane (90 mL). The
mixture was stirred vigorously for 5 h at room temperature
and diluted with dichloromethane (1000 mL). The organic
layer was decanted, and the tarry residue was washed with
dichloromethane (200 mL). The combined organic solution was
concentrated and filtered through a silica gel column (6 × 6
cm). The silica gel paste was washed with dichloromethane
until all of the product was washed out as detected by TLC.
The solvent was evaporated to give 4,5-dichloro-2-nitroben-
zaldehyde11 (14, 9.02 g, 80%) as a yellow solid: 1H NMR
(CDCl3) δ 10.40 (s, 1H), 8.27 (s, 1H), 8.05 (s, 1H).
for
C10H7Cl2N3O2‚0.5EtOH: C, 44.75; H, 3.38; N, 14.24.
Found: C, 44.72; H, 3.46; N, 14.10.
6,7-Dich lor oim id a zo[4,5-b]qu in olin -2-on e (6). (Z)-5-[(2-
Amino-4,5-dichlorophenyl)methylene]imidazolidine-2,4-di-
one (16, 4.8 g, 9.4 mmol) was dissolved in acetic acid (1000
mL) and transferred into a photochemical reaction assembly
containing a 1000 mL photochemical reaction flask, a boro-
silicate photochemical immersion well, a Pyrex sleeve, and a
450 W medium-pressure mercury-vapor lamp. A cupric sulfate/
ammonium hydroxide solution (40 g cupric sulfate pentahy-
drate and 68 mL concentrated ammonia hydroxide per liter
of water) was pumped through the photochemical immersion
well, which can filter light with wavelengths shorter than 405
nm. The filter solution was also circulated through a condenser
cooled by ice-water. In this way, the temperature of the
reaction was maintained at approximately 25 °C throughout
the reaction. The solution was irradiated by a medium-
pressure mercury lamp, with stirring, for 60 h to give a slightly
yellow suspension. The solid was collected by filtration, washed
with a small amount of acetic acid, and dried under vacuum.
The solid was then stirred in water (90 mL) and neutralized
by the addition of sodium bicarbonate. The neutralized solid
was collected by filtration, washed with water, and dried under
vacuum (0.01 mmHg/78 °C) to give 6,7-dichloroimidazo[4,5-
b]quinolin-2-one (6, 4.01 g, 90%) as a white solid: mp 262-
(Z)-5-[(4,5-Dich lor o-2-n itr op h en yl)m eth ylen e]im id a zo-
lid in e-2,4-d ion e ((Z)-15) a n d (E)-5-[(4,5-Dich lor o-2-n itr o-
p h en yl)m eth ylen e]im id a zolid in e-2,4-d ion e ((E)-15). Dry
triethylamine (3.49 mL, 25.1 mmol) was added to a suspension
of diethyl 2,4-dioxoimidazolidine-5-phosphonate10d (5.91 g, 25.1
mmol) in dry acetonitrile (40 mL) and stirred for 10 min to
give a clear solution. A suspension of 4,5-dichloro-2-nitroben-
zaldehyde (14, 5.0 g, 22.8 mmol) in dry acetonitrile (30 mL)
was added in one portion. The solution immediately became
dark brown. After the solution was stirred at room tempera-
ture for several minutes, a large amount of precipitate ap-
peared. The suspension was continuously stirred at room
temperature for an additional 1 h. The solid was collected by
filtration and washed with acetonitrile until the solid became
almost colorless. The solid was added to water (40 mL) and
stirred at room temperature for 30 min. The solid was collected
by filtration, washed with water, and dried under vacuum at
78 °C to give (Z)-5-[(4,5-dichloro-2-nitrophenyl)methylene]-
imidazolidine-2,4-dione ((Z)-15, 4.36 g, 63%): 1H NMR (DMSO-
d6) δ 11.30 (bs, 2H), 8.41 (s, 1H), 7.94 (s, 1H), 6.51 (s, 1H); 13
C
NMR (DMSO-d6) δ 164.2, 155.0, 146.1, 136.5, 132.1, 132.0,
130.6, 128.1, 126.1, 99.6. Anal. Calcd for C10H5Cl2N3O4: C,
39.74; H, 1.66; N, 13.91, Found: C, 39.80; H, 1.53; N, 13.99.
The filtrate was concentrated to about 5 mL under reduced
pressure, and water (30 mL) was added to give a slightly
yellow suspension. The solid was collected by filtration, dried
under vacuum, and recrystallized from 10 mL of 1,4-dioxane
to give (E)-5-[(4,5-dichloro-2-nitrophenyl)methylene]imidazo-
lidine-2,4-dione ((E)-15, 1.04 g, 14%) as slightly yellow
needles: 1H NMR (DMSO-d6) δ 10.84 (bs, 1 H), 10.57 (bs, 1
H), 8.37 (s, 1 H), 8.18 (s, 1H), 6.42 (s, 1 H); 13C NMR(DMSO-
d6) δ 162.9, 153.5, 146.1, 135.1, 133.7, 132.0, 130.5, 128.4,
125.5, 105.2. Anal. Calcd for C10H5Cl2N3O4: C, 39.74; H, 1.66;
N, 13.91. Found: C, 39.97; H, 1.48; N, 13.70. The mother liquor
was evaporated to dryness and gave an additional quantity of
the (Z)-15 and (E)-15 (1.5 g, 23%) mixture.
1
264 °C; H NMR (DMSO-d6) δ 11.72 (bs, 1H, D2O exchange-
able), 11.28 (bs, 1H), 8.32 (s, 1H), 8.00 (s, 1H), 7.64 (s, 1H);
13C NMR (DMSO-d6) δ 155.5, 148.4, 141.9, 128.6, 128.2, 127.9,
126.1, 126.0, 125.5, 109.1; UV [λmax, nm (ꢀ)] (MeOH) 342.0
(23 500), 334.0 (13 100), 326.6 (14 800), 228.2 (51 300); (pH 1)
351.4 (15 400), 340.6 (19 700), 251.4 (21 100), 223.8 (37 700);
(pH 11) 351.0 (20 800), 336.0 (17 600), 247.0 (59 600); MS m/z
253 (M+). Anal. Calcd for C10H5Cl2N3O: C, 47.24; H, 1.97; N,
16.53. Found: C, 47.00; H, 2.05; N, 16.39.
6,7-Dich lor o-3-(2,3,5-tr i-O-ben zoyl-â-D-r ibofu r a n osyl)-
im id a zo[4,5-b]qu in olin -2-on e (5a ). Stannic chloride (0.7 mL,
5.9 mmol) was added in one portion to a mixture of 6,7-
dichloroimidazo[4,5-b]quinolin-2-one (6, 0.5 g, 1.97 mmol) and
1-O-acetyl-2,3,5-tri-O-benzoyl-â-D-ribofuranose (TBAR) (2.98

Ribosylation of 6,7-Dichloroimidazo[4,5-b]quinolin-2-one
J . Org. Chem., Vol. 64, No. 11, 1999 4167
g, 5.9 mmol) in dry acetonitrile (60 mL). The suspension was
stirred at 50 °C for 4 h to give a clear brown solution. The
solution was diluted with ethyl acetate (300 mL), washed with
a saturated sodium bicarbonate solution (4 × 100 mL) and a
saturated sodium chloride solution (50 mL), and then dried
over anhydrous sodium sulfate. The solvent was removed
under reduced pressure, and the residue was subjected to silica
gel flash chromatography (3 × 20 cm) and eluted by 1%
methanol in chloroform. After evaporation of the solvent, the
solid was recrystallized from 2-propanol to give 6,7-dichloro-
3-(2,3,5-tri-O-benzoyl-â-D-ribofuranosyl)imidazo[4,5-b]quinolin-
2-one (5a , 1.05 g, 77%). The mother liquor was subjected again
to silica gel flash chromatography (3 × 30 cm) and eluted by
1% methanol in chloroform. The solid obtained from the
chromatography purification was recrystallized from 2-pro-
panol to give an additional 0.157 g of 5a (12%). The total
combined yield was 89%: mp 236-239 °C; 1H NMR (CDCl3) δ
9.86 (bs, 1H), 8.06-7.06 (m, 18H), 6.73 (dd, J ) 2.93, 6.01 Hz,
1H), 6.59 (q, J ) 6.6 Hz, 1H), 6.43 (d, J ) 2.9 Hz, 1H), 4.84
(dd, 1H), 4.78-4.69 (m, 2H). Anal. Calcd for C36H25Cl2N3O8:
C, 61.89; H, 3.58; N, 6.02. Found: C, 61.65; H, 3.77; N, 5.80.
6,7-Dich lor o-3-(â-D-r ibofu r a n osyl)im id a zo[4,5-b]qu in o-
lin -2-on e (5b). 6,7-Dichloro-3-(2,3,5-tri-O-benzoyl-â-D-ribo-
furanosyl)imidazo[4,5-b]quinolin-2-one (5a, 0.415 g) was stirred
in a saturated methanolic ammonia solution (100 mL) at room
temperature for 3 days. The solution was evaporated, and the
solid was triturated with hot hexane (3 × 10 mL). The hexane
was decanted, and the solid was recrystallized twice from
ethanol to give 6,7-dichloro-3-(â-D-ribofuranosyl)imidazo[4,5-
b]quinolin-2-one (5b, 0.133 g, 61%) as a white solid. The
mother liquor was subjected to silica gel flash chromatography
(2 × 10 cm) and eluted by 5% methanol in chloroform to give
an additional 0.072 g of 5b (33%) as a white solid. The total
quantity of 4a (0.13 g, 6%). The total yield of 4a (1.89 g) was
1
81%: mp 248-250 °C; H NMR (DMSO-d6) δ 12.32 (bs, 1H),
8.08-8.40 (m, 15H), 8.05 (s, 1H,), 8.01 (s, 1H), 7.66 (s, 1H),
6.37 (d, J ) 5.49 Hz, 1H), 6.25 (t, J ) 6.0 Hz, 1H), 6.11 (t, J
) 6.0 Hz, 1H), 4.88-4.69 (m, 3H). Anal. Calcd for C36H25
-
Cl2N3O8: C, 61.89; H, 3.58; N, 6.02; Found: C, 61.94; H, 3.74;
N, 5.94. Compound 5a (0.11 g, 4%) was also obtained from
flash chromatography of the mother liquor.
6,7-Dich lor o-1-(â-D-r ibofu r a n osyl)im id a zo[4,5-b]qu in o-
lin -2-on e (4b). 6,7-Dichloro-1-(2,3,5-tri-O-benzoyl-â-D-ribo-
furanosyl)imidazo[4,5-b]quinolin-2-one (4a , 3.11 g, 4.5 mmol)
was stirred in a saturated methanolic ammonia solution (300
mL) at room temperature for 24 h. The solution was evapo-
rated, and the solid was triturated with hot hexane (3 × 100
mL). The hexane was decanted, and the solid was dried under
vacuum (0.01 mmHg/78 °C) for 24 h to give 6,7-dichloro-1-(â-
D-ribofuranosyl)imidazo[4,5-b]quinolin-2-one (4b, 1.66 g, 97%)
as a white solid. A small sample was recrystallized from
methanol for analysis: mp dec above 290 °C; 1H NMR (DMSO-
d6) δ 12.17 (bs, 1H), 8.21 (s, 1H), 8.16 (s, 1H), 8.07 (s, 1H),
5.75 (d, J ) 7.25 Hz, 1H), 5.35 (d, J ) 5.88 Hz, 1H), 5.20 (t, J
) 4.70 Hz, 1H), 5.16 (d, J ) 4.42 Hz, 1H), 4.57 (q, J ) 6.18
Hz, 1H), 4.13 (m, 1H), 3.91 (d, 1H), 3.68 (m, 2H); 13C NMR
(DMSO-d6) δ 154.2, 146.9, 141.9, 129.4, 128.5, 128.1, 126.4,
125.1, 124.3, 111.9, 85.9, 85.3, 70.3, 69.7, 61.8; UV [λmax, nm
(ꢀ)] (MeOH) 342.0 (23 300), 334.0 (13 100), 327.0 (14 700), 231.0
(50 700); (pH 1) 350.8 (10 100, shoulder), 341.2 (24 000), 334.0
(17 400), 326.6 (17 100), 272.6 (50 500), 255.0 (60 800), 224.8
(94 200), 206.8 (133 000); (pH 11) 351.6 (20 400), 337.0 (17 000),
247.8 (55 000). Anal. Calcd for C15H13Cl2N3O5‚H2O: C, 44.55;
H, 3.71; N, 10.40. Found: C, 44.50; H, 3.80; N, 10.18.
6,7-Dich lor o-4-(2,3,5-tr i-O-ben zoyl-â-D-r ibofu r a n osyl)-
im id a zo[4,5-b]qu in olin -2-on e (17a ). BSA (0.07 mL, 0.29
mmol) was added to a suspension of 6,7-dichloroimidazo[4,5-
b]quinolin-2-one (6, 67 mg, 0.26 mmol) in dry acetonitrile (7
mL) and stirred for 5 min at room temperature. An additional
quantity of BSA (0.07 mL, 0.29 mmol) was added, and the
suspension became clear. This was followed by a reprecipita-
tion in a few minutes. The reaction mixture was stirred at
room temperature for an additional 30 min followed by the
addition of TBAR (0.157 g, 0.31 mmol) and TMSOTf (0.06 mL,
0.31 mmol). After the addition, the reaction flask was moved
immediately to a 50 °C oil bath. After the mixture was stirred
for 5 min, additional TMSOTf (0.06 mL, 0.31 mmol) was added,
and the reaction was stirred for an additional 10 min to give
a clear solution. The reaction solution was then diluted with
ethyl acetate (20 mL), washed with a saturated solution of
sodium bicarbonate (3 × 20 mL) and a saturated sodium
chloride solution (20 mL), and dried over anhydrous sodium
sulfate. The solvent was evaporated, and the solid was
subjected to silica gel chromatography (2 × 30 cm) and eluted
by 2% methanol in chloroform. The corresponding fraction was
collected, and the solvent was evaporated to give a solid that
was recrystallized from methanol/ethyl acetate to give 6,7-
dichloro-4-(2,3,5-tri-O-benzoyl-â-D-ribofuranosyl)imidazo[4,5-
b]quinolin-2-one (17a , 68 mg, 29%) as a white solid: mp 158-
162 °C; 1H NMR (DMSO-d6) δ 11.22 (bs, 1H), 8.55 (s, 1H), 8.25
(s, 1H), 8.0-7.44 (m, 16H), 7.15 (bs, 1H), 6.68 (m, 1H), 6.46 (t,
J ) 7.5 Hz, 1H), 4.85 (m, 1H), 4.78 (m, 1H), 4.66 (m, 1H). Anal.
Calcd for C36H25Cl2N3O8: C, 61.89; H, 3.58; N, 6.02. Found:
C, 61.62; H, 3.70; N, 5.87.
1
combined yield was 94%: mp 272-274 °C; H NMR (DMSO-
d6) δ 8.30 (s, 1H), 8.02 (s, 1H), 7.79 (s, 1H), 5.86 (d, J ) 6.23
Hz, 1H), 5.07 (bs, 3H), 5.04 (t, J ) 5.74 Hz, 1H), 4.25 (dd, J )
3.2, 5.2 Hz, 1H), 3.94 (q, 1H), 3.72 (dd, J ) 4.4, 11.8 Hz, 1H),
3.55 (dd, J ) 4.9, 11.9 Hz, 1H); 13C NMR (DMSO-d6) δ 153.8,
146.3, 140.9, 129.2, 128.3, 127.6, 126.7, 125.3, 124.5, 110.4,
85.8, 85.5, 80.0, 69.8, 62.4; UV [λmax, nm (ꢀ)] (MeOH) 343.0
(21 500), 335.4 (12 200), 327.8 (13 700), 251.0 (35 100, shoul-
der), 229.8 (47 000); (pH 1) 341.4 (22 000), 334.0 (14 200), 326.2
(15 500), 272.4 (45 500), 253.4 (55 000), 227.0 (81 800), 206.2
(116 000); (pH 11) 350.6 (21 400), 256.2 (50 100), 238.0 (46 000,
shoulder). Anal. Calcd for C15H13Cl2N3O5: C, 46.63; H, 3.37;
N, 10.88. Found: C, 46.71; H, 3.58; N, 10.50.
6,7-Dich lor o-1-(2,3,5-tr i-O-ben zoyl-â-D-r ibofu r a n osyl)-
im id a zo[4,5-b]qu in olin -2-on e (4a ). N,O-Bis(trimethylsilyl)-
acetamide (BSA, 0.85 mL, 3.6 mmol) was added to a suspen-
sion of 6,7-dichloroimidazo[4,5-b]quinolin-2-one (6, 0.85 g, 3.34
mmol) in dry 1,2-dichloroethane (60 mL). After the solution
was stirred at room temperature for 5 min, dry acetonitrile
(20 mL) and an additional quantity of BSA (0.85 mL, 3.6 mmol)
were added. The mixture was stirred at room temperature for
60 min to give a clear solution. The solution was then diluted
with dry acetonitrile (60 mL) followed by the addition of TBAR
(2.02 g, 4.0 mmol) and TMSOTf (1.6 mL, 6.7 mmol). The
solution was stirred at 70 °C for 1 h and then at room
temperature for 2 h. The reaction solution was concentrated
to 50 mL and diluted with ethyl acetate (400 mL). The solution
was washed with a saturated sodium bicarbonate solution (3
× 100 mL) and a saturated sodium chloride solution (100 mL)
and then dried over anhydrous sodium sulfate. The ethyl
acetate was removed by evaporation, and the residue was
redissolved in chloroform (100 mL). The chloroform solution
was filtered through a short silica gel column (5 × 8 cm) and
eluted by 0.5% methanol in chloroform. The solvent was
removed by evaporation, and the solid was recrystallized from
a mixture of chloroform and methanol (20 mL/5 mL) to give
6,7-dichloro-1-(2,3,5-tri-O-benzoyl-â-D-ribofuranosyl)imidazo-
[4,5-b]quinolin-2-one (4a , 1.3 g, 56%) as a white solid. The
mother liquor was then concentrated to give additional 4a
(0.46 g, 19%) as a white solid. The second mother liquor was
then subjected to silica gel flash chromatography (3 × 15 cm)
and eluted by 1% methanol in chloroform to give an additional
6,7-Dich lor o-4-(â-D-r ibofu r a n osyl)im id a zo[4,5-b]qu in o-
lin -2-on e (17b). Sodium methoxide (38 mg, 0.7 mmol) was
added to a suspension of 6,7-dichloro-4-(2,3,5-tri-O-benzoyl-
â-D-ribofuranosyl)imidazo[4,5-b]quinolin-2-one (17a , 100 mg,
0.14 mmol) in methanol (10 mL) and stirred at room temper-
ature for 30 min. Ammonium chloride (75 mg, 1.4 mmol) was
added, and the reaction mixture was continuously stirred for
a couple of minutes. The reaction mixture was diluted with
ethyl acetate, washed with water (2 × 40 mL), a saturated
sodium bicarbonate solution (40 mL), and a saturated sodium
chloride solution (20 mL), and dried over anhydrous sodium
sulfate. The solvent was evaporated, and the solid was
triturated with hexane (3 × 10 mL). The hexane was decanted,
and the solid was dried under 0.01 mmHg/78 °C for 24 h. The

4168 J . Org. Chem., Vol. 64, No. 11, 1999
Zhu et al.
solid was then recrystallized from methanol to give 6,7-
dichloro-4-(â-D-ribofuranosyl)imidazo[4,5-b]quinolin-2-one (17b,
30 mg, 48%) as a white solid: mp dec above 200 °C; 1H NMR
(DMSO-d6) δ 11.087 (bs, 1H), 8.63 (s, 1H), 8.22 (s, 1H), 7.40
(s, 1H), 6.73 (d, J ) 7.3 Hz, 1H), 5.54 (t, 1H), 5.36 (d, J ) 6.6
Hz, 1H), 5.3 (d, J ) 5.2 Hz, 1H), 4.76 (q, J ) 6.6, 1H), 4.23 (m,
1H), 4.08 (m, 1H), 3.69 (m, 2H); 13C NMR (DMSO-d6) δ 165.2,
160.1, 132.5, 131.6, 129.5, 129.0, 126.3, 123.8, 119.3, 106.6,
91.6, 86.8, 70.2, 69.5, 61.1; UV [λmax, nm (ꢀ)]: (MeOH) 363.8
(16 200), 346.4 (16 600), 331.4 (10 700), 241.0 (23 800, shoul-
der), 227.2 (27 900); (pH 1) 351.0 (12 900), 340.8 (15 700), 253.0
(25 900), 223.8 (45 200); (pH 11) 362.8 (16 800), 346.4 (17 300),
238.5 (23 000), 209.0 (33 500). Anal. Calcd for C15H13Cl2N3O5‚
1.5H2O: C, 43.58; H, 3.87; N, 10.16. Found: C, 43.89; H, 3.70;
N, 9.86.
Gen er a l P r oced u r e for th e Tr a n sglycosyla tion of 17a .
BSA (2 equiv) was added to a solution of 6,7-dichloro-4-(2,3,5-
tri-O-benzoyl-â-D-ribofuranosyl)imidazo[4,5-b]quinolin-2-one
(17a ) in 1,2-dichloroethane and acetonitrile (3/4), and the
reaction solution was stirred at room temperature for 1 h. The
Lewis acid (2 equiv) was added, and the reaction solution was
stirred at 70 °C for 1 h. The reaction solution was diluted with
ethyl acetate, and the organic solution was washed with a
saturated sodium bicarbonate solution and a saturated sodium
chloride solution and dried over anhydrous sodium sulfate. The
solvent was evaporated, and the residue was subjected to silica
gel chromatography with elution by chloroform. The fractions
containing nucleoside components were collected and com-
bined. The solvent was evaporated, and the ratio of 4a and
5a was determined by HPLC.
When 17a was treated with BSA and, subsequently, TM-
SOTf, 4a and 5a (14.7/1, 83% combined yield) were obtained.
When 17a was treated with BSA and, subsequently, stannic
chloride, 4a and 5a (4.7/1, 86% combined yield) were obtained.
6,7-Dich lor o-1-(2,3,5-tr i-O-ben zoyl-â-D-r ibofu r a n osyl)-
4-(2,3,5-t r i-O-b en zoyl-â-D-r ib ofu r a n osyl)im id a zo[4,5-b]-
qu in olin -2-on e (19a ). BSA (0.036 mL, 0.14 mmol) was added
to a suspension of 6,7-dichloro-4-(2,3,5-tri-O-benzoyl-â-D-ribo-
furanosyl)imidazo[4,5-b]quinolin-2-one (17a , 50 mg, 0.072
mmol) in dry acetonitrile under an argon atmosphere and
stirred at room temperature for 1 h to give a clear colorless
solution. TBAR (55 mg, 0.11 mmol) was added followed by the
addition of TMSOTf (0.017 mL, 0.088 mmol). After being
stirred at room temperature for 3 h, the reaction solution was
diluted with dichloromethane (30 mL), washed sequentially
with saturated sodium bicarbonate (3 × 20 mL) and saturated
sodium chloride (20 mL), and dried over anhydrous sodium
sulfate. The solvent was evaporated under reduced pressure,
and the residue was subjected to silica gel chromatography (2
× 11 cm) with elution by chloroform. The appropriate fractions
were collected, and the solvent was evaporated to give 6,7-
dichloro-1-(2,3,5-tri-O-benzoyl-â-D-ribofuranosyl)-4-(2,3,5-tri-
O-benzoyl-â-D-ribofuranosyl)imidazo[4,5-b]quinolin-2-one (19a ,
22 mg, 27%) and 4a (6 mg, 5%) with a recovery of 17a (25 mg,
50%). In a separate experiment, when the reaction was stopped
after 3.5 h, 19a (35 mg, 42%), 4a (13 mg, 26%), and 17a (9
mg, 18%) were isolated using the same workup procedure. A
small amount of 19a was recrystallized from methanol/
1
chloroform for analysis: mp 128-132 °C; H NMR (CDCl3) δ
8.30-7.36 (m, 31H), 7.2 (s, 1H), 7.02 (d, J ) 4.7 Hz, 1H), 6.57
(m, 1H), 6.46 (s, 1H), 6.43 (dd, 1H), 6.29 (t, J ) 6.9 Hz, 1H),
6.1 (m, 2H), 4.91 (m, 2H), 4.76 (m, 4H). Anal. Calcd for C62H45
-
Cl2N3O15‚2MeOH: C, 63.68; H, 4.39; N, 3.48. Found: C, 63.76;
H, 4.52; N, 3.34.
6,7-Dich lor o-1-(â-D-r ibofu r an osyl)-4-(â-D-r ibofu r an osyl)-
im id a zo-[4,5-b]qu in olin -2-on e (19b). 6,7-Dichloro-1-(2,3,5-
tri-O-benzoyl-â-D-ribofuranosyl)-4-(2,3,5-tri-O-benzoyl-â-D-ri-
bofuranosyl)imidazo[4,5-b]quinolin-2-one (19a , 90 mg, 0.079
mmol) and sodium methoxide (90 mg, 1.7 mmol) in methanol
(10 mL) were stirred at room temperature for 15 min. Am-
monium chloride (99 mg, 1.8 mmol) was added, and the
reaction solution was stirred for an additional 3 min. The
reaction solution was directly absorbed on a small amount of
silica gel and subjected to silica gel chromatography (2.5 × 4
cm) with elution by 14% of methanol in chloroform. The
appropriate fractions were collected, and the solvents were
evaporated to give 6,7-dichloro-1-(â-D-ribofuranosyl)-4-(â-D-
ribofuranosyl)imidazo[4,5-b]quinolin-2-one (19b, 27 mg, 66%)
as a white solid. A small amount of sample was recrystallized
1
from methanol and water for analysis: mp dec >250 °C; H
NMR (DMSO-d6) δ 8.76 (s, 1H), 8.15 (s, 1H), 7.92 (s, 1H), 6.80
(d, J ) 7.4 Hz, 1H, H1′), 5.69 (d, J ) 7.2 Hz, 1H, H1′′), 5.48 (t,
1H, D2O exchangeable), 5.41 (d, 1H, D2O exchangeable), 5.32
(m, 2H, D2O exchangeable), 5.14 (m, 2H, D2O exchangeable),
4.72 (q, 1H, H2′), 4.51 (q, 1H, H2′′), 4.25 (m, 1H, H3′), 4.1 (m,
1H, H3′′), 4.05 (q, 1H, H4′), 3.88 (q, 1H, H4′′), 3.69 (m, 4H);
13C NMR (DMSO-d6) δ 163.1, 159.7, 131.2, 130.3, 130.1, 129.1,
126.5, 123.3, 119.6, 109.5, 91.4, 86.6, 86.0, 84.9, 70.3, 70.0, 69.9,
69.2, 61.7, 60.7; MS FAB m/z 518 ([M + H]+, 7.4; HRMS calcd
for C20H22Cl2N3O9 518.0733, found 518.0724.
Con ver sion of Com p ou n d 19a to 4a . TMSOTf (0.005 mL,
0.025 mmol) was added to a solution of 19a (17 mg, 0.015
mmol) in dry acetonitrile/1,4-dichloroethane (0.8 mL/0.6 mL),
and the solution was stirred at room temperature for 5 min.
TLC indicated a complete disappearance of 19a . The product
was purified by the normal method (see the synthesis of 4a )
to give 4a (9.4 mg, 90%).
Ack n ow led gm en t. This work was supported by
research grant U19-AI-31718 from the National Insti-
tute of Allergy and Infectious Disease, National Insti-
tutes of Health. We should also like to thank Ms.
Marina Savic and Ms. Kim Barrett for the preparation
of this manuscript.
Su p p or tin g In for m a tion Ava ila ble: The carbon-13 as-
signments of compounds 4b and 5b in the aromatic region by
using the selective long-range 13C-1H decoupling method. This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O982084O